Targeting mitochondrial 18kDa Translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype

The aim of this study was to establish mitochondrial cholesterol trafficking 18kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically, and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR, immunoblotting and radiolabelling, including [3H]cholesterol efflux to apoA-I, HDL and human serum. Induction of macrophage cholesterol deposition by acetylated LDL (AcLDL) increased expression of TSPO mRNA and protein, reflecting findings in human carotid atherosclerosis. Transient overexpression of TSPO protein enhanced efflux (E%) of [3H]cholesterol to ApoA-I, HDL and human serum, compared with empty vector controls, while gene knockdown of TSPO achieved the converse. Ligation of TSPO (PK11195, FGIN-1-27, flunitrazepam) triggered increases in [3H]cholesterol efflux, an effect which was amplified in TSPO overexpressing macrophages. Overexpression of TSPO induced expression of genes (PPARA, NR1H3, ABCA1, ABCG4, APOE) and proteins (ABCA1, PPARa) involved in cholesterol efflux, reduced macrophage neutral lipid mass and lipogenesis, and limited cholesterol esterification following exposure to AcLDL. Thus, targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation, via enhanced cholesterol efflux to (apo)lipoprotein acceptors.

Source: Clinical Science - May 12, 2014 Category: Biomedical Science Authors: J M W Taylor, A Marie Allen, A Graham Source Type: research